Cardinal symptoms in Parkinson's disease (PD) result primarily from death of dopaminergic (DA) neurons in substantia nigra (SN)1,2. Current interventions ameliorate symptoms but there is no treatment to halt or delay loss of DA neurons. Several findings indicate that respiratory chain dysfunction is directly involved in the pathogenesis of PD1.2. However, the supporting data are either correlative or based on neurotoxin and drug treatments that may have pleiotropic effects. In this proposal, we will attempt to validate a new and unique model of PD in mice. If successful, studies on this model could directly test the hypothesis that respiratory chain dysfunction in DA neurons can induce cardinal features of PD. This model could also test the hypothesis that bioenergetic failure will increase the formation of reactive oxygen species (ROS), which will contribute to degeneration of respiratory chain deficient DA neurons. The specific aims are: 1. To generate tissue-specific knockout mice with disruption of oxidative phosphorylation in DA neurons. 2. To determine if respiratory chain dysfunction in DA neurons will induce a PD like phenotype and validate this approach as a new and unique model of Parkinson's Disease.